January 2021 - Inserm Newsroom

Better Access to Education Reduces Differences in Cognitive Capacity Between Men and Women

Posted on January 29, 2021November 23, 2022 by Graziella Cara

From one generation of women to the next, access to higher education is linked to an improvement in certain cognitive aspects. © Adobe Stock

Elderly women are currently at a higher risk than men of developing dementia, particularly Alzheimer’s disease. A phenomenon that could partially be explained by inequalities in access to education between the sexes during the first half of the 20th century. Researchers from Inserm and Université de Paris, in collaboration with University College London, have shown that certain cognitive capacities have improved in women over recent generations, and that this is linked to a larger number of women accessing higher education. In the longer term, they believe that sex-based inequalities in dementia risk could decrease. Their study has been published in The Lancet Public Health.

Elderly women currently have a 50% higher risk than their male counterparts of developing Alzheimer’s disease – a condition for which several risk factors are already well known, such as cardiovascular disease and level of education. It was the latter risk factor that Inserm researcher Séverine Sabia and the EpiAgeing team from the Center for Research in Epidemiology and Statistics at Université de Paris decided to study.

The current generation of very elderly people was born between 1920 and 1940, a time when few women had access to higher education.

However, from the 1960s, things began to change, with greater numbers of women accessing universities and on a more equal footing with men, to an extent that their educational attainment has more or less caught up with that of men in developed countries. A development that Sabia and her colleagues believe could reduce sex-based differences in dementia risk in the years to come.

To test this hypothesis, they compared the cognitive capacities during aging of women and men according to their education levels over several generations. These individuals were participants in two British cohorts – ELSA (English Longitudinal Study of Ageing) and Whitehall II – which had enrolled a total of 15,924 people from the general population, born between 1930 and 1955. The researchers divided them into three subgroups according to their year of birth: 1930-38, 1939-45, and 1946-55. The education level of the various participants was also known.

For each participant, two components of cognitive function were assessed several times over the 1997-2015 follow-up period. The first was short-term memory, which involves remembering a list of words just heard, followed by verbal fluency, which is the ease at which a person can produce words by naming as many animals (for example) as possible in one minute. “This is the first time to my knowledge that research of this type has focused on cognitive trajectories during aging in men and women combined with changes in education level in successive generations,” explains Sabia.

In both cohorts, the overall education level was higher in the youngest group (born between 1946 and 1955) than in the oldest group (born between 1930 and 1938). In addition, the proportion of women with a level equivalent to that of the high school diploma more than doubled, increasing from 14% to 33% (compared to 36% and 54% for men).

Data from this study suggest that women’s memory capacity has improved in recent years. They outperformed men in the tests at all ages, with the gap widening yet further among the “youngest” generation. In terms of verbal fluency, while men fared better than women in the oldest group born between 1930 and 1938, this gap narrowed for the participants born more recently, with the opposite effect being observed for the generation born between 1946 and 1955.

“At the same level of education, women are at absolutely no disadvantage compared to men when it comes to memory or verbal fluency,” clarifies Mikaela Bloomberg, first author of the study.

“Although we studied just two of the components of cognitive function, the trend here is indicative of better cognitive reserve in women born more recently, thanks in part to improved access to higher education. This could ultimately result in a reduction in male/female differences in dementia risk in countries where access to education is similar regardless of sex.

These findings therefore underline the importance of access to education for all in order to promote aging in good health,” concludes Sabia.

Covid-19: Understanding Early Immune Response

Posted on January 28, 2021November 23, 2022 by Graziella Cara

Cellule infectée par le SARS-CoV-2. © Sébastien Eymieux et Philippe Roingeard, INSERM – Université de Tours

As the COVID-19 pandemic continues, scientists are making significant headway in understanding the transmission of the SARS-CoV-2 coronavirus and the immune response it triggers at the time of infection. Researchers from Inserm, the Paris hospitals group AP-HP and Université de Paris, in collaboration with Rockefeller University in New York, have provided new data on the very early stages of immune response. Their findings have been published in Journal of Experimental Medicine.

Understanding the immune response against SARS-CoV-2 is essential if we are to know who is at risk of developing severe forms of COVID-19 and how to treat them effectively. While many studies have been conducted in patients in the advanced stages of infection, when they are already showing signs of severity, little is known about the very early stages of immune response against the virus.

Thanks to close collaboration between the Inserm teams of Ali Amara, virologist, and Vassili Soumelis, immunologist at Saint-Louis Research Institute (Université de Paris/Inserm/AP-HP), a study published in the Journal of Experimental Medicine was able to characterize innate immune response[1] within 24 to 48 hours following contact with the SARS-CoV-2 virus.

The researchers used immune cells called “plasmacytoid predendritic cells” as a model of innate immune cells that play an essential role in antiviral immunity by producing large amounts of interferon-alpha[2].

They reconstructed the early immune response to the virus by placing these model cells in contact with primary strains of SARS-CoV-2 isolated from patients with COVID-19.

Analysis of this in vitro reconstituted response showed that SARS-CoV-2 induced effective and complete activation of the plasmacytoid predendritic cells. These then produced large amounts of interferon-alpha (the first line of defense against viruses) and differentiated into dendritic cells capable of activating T cells (which correspond to specific immunity cells). The researchers were also able to show that this activation of the plasmacytoid predendritic cells was partially inhibited by hydroxychloroquine, which would call for caution in the use of this molecule.

In the second part of the study, the teams collaborated with Jean-Laurent Casanova’s team from the Imagine Institute (Inserm/Université de Paris/AP-HP) and Rockefeller University in New York, in order to study the response of plasmacytoid predendritic cells from patients with genetic deficits for certain important genes of innate immunity. The objective was to clarify the molecular mechanisms involved in the response of these immune cells to SARS-CoV-2.

These experiments performed on samples obtained directly from patients showed that the response of plasmacytoid predendritic cells is dependent on UNC93B and IRAK-4, two important molecules of innate antiviral immunity. This research as a whole makes it possible to clarify early immune response to SARS-CoV-2 as well as some of its molecular determinants.

The study suggests that the immune system is naturally armed to respond to SARS-CoV-2 and that defects in the response of plasmacytoid predendritic cells, particularly in the early production of interferon-alpha, may contribute to the infection progressing to a severe form.

[1] Innate immunity is the body’s first line of defense and is triggered as soon as the body is exposed to a bacterium or virus (such as SARS-CoV-2). The innate immunity cells can contribute to the total destruction of the detected microbes or present them to the mechanisms of acquired immunity to facilitate their destruction by specific mechanisms (T and B cells).

[2] Interferons are cytokines (proteins) whose production is induced following viral, bacterial or parasitic infection, or the presence of tumor cells. While their main function is to interfere with viral replication, they also have an antibacterial and antiproliferative action, as well as an activating effect on other immune cells.

Discovery stops testing Remdesivir against Covid-19 for lack of evidence of its efficacy

Posted on January 27, 2021November 23, 2022 by Graziella Cara

©hal-gatewood-AypaEmWVH8I-unsplash

The Discovery trial was originally launched in March 2020 by Inserm to evaluate possible treatments for COVID-19. Its European expansion (Discovery Europe) was made possible by the EU-RESPONSE[1] project funded by the European Commission (see details in the box below). On January 13^th, 2021, the Discovery Europe trial Data Safety Monitoring Boards (DSMB) evaluated an interim report based on 776 patients of whom 389 received remdesivir and 387 received standard of care. The efficacy of the treatment was evaluated after 15 days and measured on the WHO-7-point ordinal scale. As a result of the evaluation, the DSMB recommended that patient recruitment be suspended.

This recommendation was based on lack of evidence of efficacy of remdesivir after 15 days and a very low probability to conclude with the inclusion of additional participants. There was also no evidence for treatment efficacy at day 29 (on the same scale or on mortality), nor in the analysis restricted to moderate-risk participants at day 15. This recommendation has been endorsed by the Discovery Europe Steering Committee.

Discovery researchers are now collecting and monitoring data on all participants enrolled in the clinical study in order to publish their detailed scientific findings in a peer reviewed scientific journal.

The Discovery Europe trial will continue in 80 centres from 14 European countries and will soon launch the clinical evaluation of a combination of two monoclonal antibodies. Beside the deployment of vaccines, it remains paramount to provide strong evidence for adding effective medicines for the treatment of patients affected by Covid-19.

The Discovery trial was originally launched in March 2020 by Inserm to evaluate possible treatments for Covid-19. An agreement was signed with the WHO Solidarity trial so that it became an add-on trial of Solidarity. Discovery is now part of the EU-RESPONSE project (Discovery Europe), funded through Horizon 2020, the EU’s research and innovation programme. It is a multicentre adaptative randomized platform trial for the evaluation of the clinical and virological efficacy, as well as the safety, of candidate treatment versus standard of care in hospitalized adult patients with laboratory confirmed Covid-19. The initial set of tested treatments includes lopinavir/ritonavir, lopinavir/ritonavir plus IFN-b-1a, hydroxychloroquine, and remdesivir. The primary endpoint is the clinical status at day 15, measured on the WHO 7-point ordinal scale..

In June 2020, the DSMBs of Solidarity recommended to stop the hydroxychloroquine arm for futility concern as well as both lopinavir/ritonavir containing arms for futility and safety concern. In July 2020, continuing the evaluation of remdesivir, approved for conditional marketing authorisation in the European Union, was felt important because more data were needed to fully assess its efficacy.

[1] https://cordis.europa.eu/project/id/101015736

À l’Inserm, la lutte contre la pandémie de Covid-19 se poursuit

Posted on January 25, 2021November 23, 2022 by Léa Surugue

The “Cocktail Effect” of Endocrine Disruptors Better Understood

Posted on January 13, 2021November 23, 2022 by Graziella Cara

The PXR receptor has a large cavity made up of four pockets (shown in blue, orange, purple and red), which can accommodate several endocrine disruptors at once (their color corresponds to that of the pocket in which they bind). © Vanessa Delfosse

Endocrine disruptors can potentially become more harmful if mixed. Following on from research published in 2015, scientists from Inserm, Université de Montpellier and CNRS at the Structural Biology Center and Montpellier Cancer Research Institute continue to decipher the molecular mechanisms behind this phenomenon known as the “cocktail effect”. While their research provides a better understanding of the complex interactions between endocrine disruptors and the body, it is still in its infancy and must be continued in order to define the real impact of these combinations on human health. Their new study has been published in the journal PNAS.

Scientists continue to elucidate the health effects of environmental pollutants, such as pesticides, residues from medicines, or chemical compounds used in cosmetics and food products. Some of these substances are capable of binding to receptors that are present in or on human cells, in the place of endogenous molecules.

It is at this point that these compounds are referred to as “endocrine disruptors” and may present a risk if they lead to the disruption of certain physiological mechanisms.

The toxicity of several such compounds has already been documented – for example bisphenol A, the exposure to which is linked to an increased risk of certain cancers, metabolic disorders and reduced fertility, or phthalates, which can impair reproductive function.

Researchers are also studying the “cocktail effect”, which is the effect that a mixture of these different substances can have on health. An essential endeavor, given the permanent presence of hundreds of endocrine disruptors in the environment. They rarely act in isolation on human health, but add up and form combinations that can in some cases be harmful.

Two Montpellier-based teams led by Inserm researchers William Bourguet and Patrick Balaguer at the Structural Biology Center (Inserm/CNRS/Université de Montpellier) and the Cancer Research Institute (Inserm/Université de Montpellier) had already discovered that certain endocrine disruptors, which in principle are harmless individually at doses found in the environment, can in some cases be more harmful if mixed.

The scientists had previously shown that two of these compounds, namely 17α-ethinylestradiol (used in certain birth control pills) and TNC (a banned organochlorine pesticide that persists in soils), can bind simultaneously to the same receptor present in the cell nucleus. This receptor, called PXR, controls the expression of different genes involved in regulating various physiological functions.

By binding to this receptor, each of these two endocrine disruptors attracts the other, increasing the amount of product that is bound. An effect that is referred to as “synergistic”, meaning that the function of PXR is altered at much lower doses with this combination of substances than with the individual components, and with a potentially toxic effect.

New advances in the understanding of the molecular mechanism

In the new study published in PNAS[1], the researchers went further in understanding this phenomenon by using a method called “crystallography” which makes it possible to observe chemical bonds at the atomic scale, as well as cellular models and in vivo amphibian models. They studied the interactions between the PXR receptor and 13 endocrine disruptors, alone and then in pairs, selected for their affinity with the receptor, their chemical diversity, and their persistence in the environment. The researchers also looked at the impact of these interactions on PXR activity and on the expression of the genes it controls.

They discovered that the PXR receptor actually has four pockets with specific molecular and physico-chemical characteristics. This allows substances with very different structures to interact with and bind to it simultaneously. In addition, PXR exhibits a high level of plasticity, enabling the binding of various unexpected combinations of molecules. By studying the expression of the genes controlled by PXR for each pair of endocrine disruptors that can bind to it, the research teams found that only certain combinations have a strong synergistic effect.

In addition, the researchers also looked at another receptor, RXR, with which PXR combines in order to bind to DNA and regulate gene expression. Using a combination of three endocrine disruptors, they found that the activation of RXR by one of the compounds further reinforced the synergistic effect of the other two PXR-linked disruptors. This mechanism therefore further increases the toxicity of the mixtures.

“This research enabled us to deepen our understanding of the cocktail effect of endocrine disruptors: molecules with a highly variable structure can interact indirectly within the body to obtain mixtures that are toxic to health in both in vitro and animal models, explains William Bourget. And this is just the beginning: while we have discovered a mechanism that explains some of the synergies, these interactions remain complex and others probably exist. These findings do not at this stage make it possible to predict the real impact of these combinations on human health“, he warns.

Although this research focused on PXR, other receptors in cells resemble it and will be the subject of future research by the teams. Ultimately, they hope to elucidate the extent of the phenomenon and above all be able to predict the harmful cocktail effects of several endocrine disruptors. “We are tackling this by combining artificial intelligence with our algorithms. It works for some substances taken alone, but more research is needed into the cocktail effects, which are still very difficult to predict”, concludes Bourguet.

[1] The Molecular Physiology and Adaptation laboratory (MNHN/CNRS) and the Hubert-Curien Multidisciplinary Institute (CNRS/Université de Strasbourg) also participated in this new research.

A New Mechanism Involved in the Development of Persistent Bacterial Infections

Posted on January 4, 2021November 23, 2022 by Graziella Cara

So-called “persistent” bacterial infections constitute a major public health problem and are linked to significant failures of antibiotic treatments. Researchers from Inserm and Université de Rennes 1, in collaboration with a team based in Switzerland, have identified a new mechanism to explain the persistence of Staphylococcus aureus. Their research has been published in Nature Microbiology.

In this context, persistence denotes the ability of bacteria to survive high doses of antibiotics without actually becoming resistant. They become persistent by slowing their growth – a bit like going into “hibernation” – to protect themselves from antibiotic treatments. The presence of such antibiotic-tolerant bacteria represents a major public health problem. When the intake of antibiotics is stopped, some of the bacteria “wake up” and are liable to multiply again, presenting a very high risk of relapse or of developing a chronic bacterial infection.

Many of the mechanisms leading to the formation of persistence remain unknown. In their study, the Inserm and Université de Rennes 1 researchers at the Bacterial Regulatory RNAs and Medicine laboratory focused on Staphylococcus aureus. This bacterium is the leading pathogen responsible for nosocomial infections (infections contracted in hospital) and is also implicated in many cases of food poisoning.

Fighting chronic bacterial infections

In their study, the researchers focused on a Staphylococcus aureus non-coding RNA, i.e. one that is not translated into proteins.

They have shown that once positioned on the ribosomes[1] of the staphylococci, this RNA (referred to as SprF1 antitoxin) reduces protein synthesis during the growth of the bacterium (the aforementioned “hibernation” phenomenon). This mechanism promotes the formation of persistent staphylococci that become insensitive to antibiotics.

“We have revealed an RNA-guided molecular process in which the interaction between this SprF1 RNA and the ribosome is involved in the formation of antibiotic-tolerant bacteria, which are themselves largely implicated in chronic staphylococcal infections,” emphasizes Brice Felden, the professor at Université de Rennes 1 who supervised this work.

These findings also make it possible to envisage a new class of anti-infectives that target persistent bacteria, and thus new treatments for chronic Staphylococcus aureus infections. “Based on these results, we want to develop molecules that fight the persistent bacteria by targeting the SprF1 antitoxin. This strategy is therefore aimed at supplementing the therapeutic arsenal available to clinicians, who find themselves confronted with an increasing number of cases of chronic bacterial disease,” declares Marie-Laure Pinel-Marie who coordinated this research.

These findings have been the subject of a European patent application.

[1] Particles present in all cells that are the “factories” for making proteins.

Inserm Newsroom - Press room of the French national institute of health and medical research

Month: January 2021